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Dose-finding Study (dose-finding + study)
Selected AbstractsA phase I clinical trial of the histone deacetylase inhibitor belinostat in patients with advanced hematological neoplasiaEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 3 2008Peter Gimsing Abstract Purpose:, To determine the safety, dose-limiting toxicity and maximum tolerated dose (MTD) of the novel hydroxamate histone deacetylase inhibitor belinostat (PXD101) in patients with advanced hematological neoplasms. Patients and methods:, Sequential dose-escalating cohorts of three to six patients with hematological malignancies received belinostat administered as a 30-min i.v. infusion on days 1,5 of a 21-d cycle. Experience from a parallel dose-finding study in patients with solid tumors influenced the selection of the final dose. Results:, Sixteen patients received belinostat at one of three dose levels: 600 mg/m2/d (three patients), 900 mg/m2/d (three patients) and 1000 mg/m2/d (10 patients), the dose determined to be the MTD in a phase I solid tumor study [Steele et al. (2008) Clin Cancer Res, 14, 804,10]. The most common treatment-related adverse events (all grades) were nausea (50%), vomiting (31%), fatigue (31%) and flushing (31%). No grade 3 or 4 hematological toxicity compared with baseline occurred except one case of grade 3 lymphopenia. There were two related grade 4 adverse events of renal failure observed. Both events occurred in patients with multiple myeloma and had similar characteristics, i.e. an acute episode of decrease in renal function (pre-existing nephropathy in one patient), with a metabolic profile and decrease in tumor burden consistent with tumor lysis syndrome. No other related grade 4 events were noted. The only related grade 3 events noticed in more than one patient were fatigue and neurological symptoms (one patient had status epilepticus in association with uremia and one patient had paresthesia), all other related grade 3 events occurred in single patients. No cardiac events were noted. No complete or partial remissions were noted in these heavily pre-treated (median of four prior regimens) patients. However, five patients, including two patients with diffuse large-cell lymphoma [including one patient with transformed chronic myelomcytic leukaemia (CLL)], two patients with CLL and one patient with multiple myeloma, achieved disease stabilization in of two to nine treatment cycles. Conclusions:, Intravenous belinostat at 600, 900 and 1000 mg/m2/d is well tolerated by patients with hematological malignancies. The study was carried out in parallel to a similar dose-finding study in patients with solid tumors, in which the MTD was determined to be 1000 mg/m2/d days 1,5 in a 21-d cycle. This dose can also be recommended for phase II studies in patients with hematological neoplasms. [source] Acute effects of exposure to vapours of standard and dearomatized white spirits in humans.JOURNAL OF APPLIED TOXICOLOGY, Issue 3 2009Abstract A move from ,standard' white spirit (stdWS, 15,20% aromatics) to low-aromatic or dearomatized white spirit (deWS) has been seen, as the latter are considered to carry a smaller risk of health effects. However, data on health risks of deWS on humans are sparse. The aim of this dose-finding study was to identify thresholds of irritation and central nervous system (CNS) effects of the two types of white spirit, as a basis for more detailed studies. Four female and four male healthy volunteers rated symptoms related to irritation, smell and CNS effects on a 0,100 mm visual analogue scale while exposed to increasing levels of deWS or stdWS in eight 10 min steps from 0.5 to 600 mg m,3. Combined ratings of questions related to irritation revealed statistically significant increases compared with pre-exposure ratings at 50 mg m,3 and higher exposures. The ratings increased in a dose-dependent fashion, the medians reaching ,somewhat' for stdWS and ,hardly at all' for deWS. Higher ratings of irritation were found during exposure to stdWS compared with deWS, reaching significance only at 500 mg m,3. The combined ratings of CNS effects reached ,hardly at all', and were significantly increased only for stdWS at 500 and 600 mg m,3. Copyright © 2008 John Wiley & Sons, Ltd. [source] Safety and efficacy of a single bolus administration of recombinant factor VIIa in liver transplantation due to chronic liver disease,LIVER TRANSPLANTATION, Issue 8 2005Raymond M. Planinsic Orthotopic liver transplantation (OLT) can be associated with excessive blood loss. As a result, there may be increased risk of adverse outcomes. Activated recombinant factor VII (rFVIIa) has demonstrated the ability to improve hemostasis in a variety of disorders; however, there has been a limited amount of research into its use in OLT. The purpose of this dose-finding study was to examine the efficacy and safety of rFVIIa in the reduction of bleeding in patients undergoing OLT. In this double-blind trial, patients with end-stage liver disease scheduled for OLT were randomized to 1 of 4 parallel study groups. They received a single intravenous bolus of rFVIIa (20, 40, or 80 ,g/kg) or placebo prior to surgery. The primary assessment endpoint was the total number of red blood cell (RBC) units transfused perioperatively. Safety was evaluated by adverse events reported. Eighty-three comparable patients were randomized to receive study product, with 82 ultimately undergoing OLT. There were no significant differences in required RBC units between the placebo and rFVIIa study groups. The number of adverse events was comparable between study groups. In conclusion, rFVIIa has a good safety profile in patients undergoing OLT. However, the doses studied did not have any effect on the number of RBC transfusions required. (Liver Transpl 2005;11:895,900.) [source] Placebo-controlled, double-blind dose-finding study of entacapone in fluctuating parkinsonian patients,MOVEMENT DISORDERS, Issue 1 2007Yoshikuni Mizuno MD Abstract We conducted a multicenter randomized, placebo-controlled double-blind parallel-group study in Japanese Parkinson's disease (PD) patients with wearing-off motor fluctuations to determine the clinical efficacy and safety of entacapone as an adjunct to concomitant treatment with levodopa and a dopa decarboxylase inhibitor (DCI). We randomized 341 patients to receive entacapone 100 or 200 mg or placebo per dose of levodopa/DCI for 8 weeks. The primary efficacy variable was on time change while awake, determined by patients' diaries. Mean baseline on time in each group was approximately 8 hours. Mean on time change at final assessment was 1.4 hours each for entacapone 100-mg and 200-mg groups and by 0.5 hours for the placebo group (P < 0.05). The two entacapone doses were equally efficacious. Adverse events occurred in 79 patients (69.9%) in placebo, 82 (72.6%) in 100 mg, and 98 (86.0%) in 200 mg. The most common adverse event with entacapone was an increase in dyskinesias. The overall safety profile was satisfactory in both entacapone groups. In conclusion, both entacapone 100 and 200 mg were equally effective in increasing on time of PD patients with wearing-off fluctuations, although the safety and tolerability profile appeared more favorable for the 100-mg dose. © 2006 Movement Disorder Society [source] Comparison of three single doses of mifepristone as emergency contraception: a randomised controlled trialAUSTRALIAN AND NEW ZEALAND JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Issue 6 2005Jie JIN Abstract Background:, This is an analysis of the Australian component of a large World Health Organization multicentre dose-finding study of mifepristone for emergency contraception and the first clinical study of this controversial drug in Australia. Aims:, To compare the effectiveness and side-effects of three single doses of mifepristone taken within 120 h after unprotected coitus as emergency contraception. Design:, Double-blind, randomised controlled trial. Subjects and methods:, One hundred fifty healthy women with regular menstrual cycles who requested emergency contraception. Participants were allocated randomly to one of the three doses (10, 50 and 600 mg). The primary outcome was confirmed pregnancy, and secondary outcome measures included side-effects and delay in the onset of the next menses. Results:, Pregnancy rates for mifepristone 10, 50 and 600 mg were 2.0, 2.1 and 2.1%, respectively, with no significant difference between groups. No major side-effects occurred, except an unpredictable delay in the onset of the next menses. Mifepristone 600 mg caused a significantly longer delay in the onset of the next menses than either the 10 or the 50 mg dose. Conclusion:, Lowering the dose of mifepristone from 600 to 10 mg did not significantly impair its effectiveness as an emergency contraceptive, and caused less delay in the onset of the next menses. Therefore, a dose as low as 10 mg may be preferable to 600 mg for emergency contraception. This is very much lower than the dose required to terminate a pregnancy. [source] Continual Reassessment Method for Ordered GroupsBIOMETRICS, Issue 2 2003John O'Quigley Summary We investigate the two-group continual reassessment method for a dose-finding study in which we anticipate some ordering between the groups. This is a situation in which, for either group, we have little or almost no knowledge about which of the available dose levels will correspond to the maximum tolerated dose (MTD), but we may have quite strong knowledge concerning which of the two groups will have the higher level of MTD, if indeed they do not have the same MTD. The motivation for studying this problem came from an investigation into a new therapy for acute leukemia in children. The background to this study is discussed. There were two groups of patients: one group already received heavy prior therapy while the second group had received relatively much lighter prior therapy. It was therefore anticipated that the second group would have an MTD higher or at least as high as the first. Generally, likelihood methods or, equivalently, the use of noninformative Bayes priors, can be used to model the main aspects of the study, i.e., the MTD for one of the groups, reserving more informative Bayes modeling to be applied to the secondary features of the study. These secondary features may simply be the direction of the difference between the MTD levels for the two groups or, possibly, information on the potential gap between the two MTDs. [source] Efficacy and tolerability of EPs 7630 in patients (aged 6,18 years old) with acute bronchitisACTA PAEDIATRICA, Issue 4 2010A randomized, double-blind, placebo-controlled clinical dose-finding study Abstract Aim:, For EPs-7630, a herbal drug preparation from Pelargonium sidoides roots, therapeutic effects in respiratory tract infections outside the strict indication for antibiotics have already been demonstrated in adults. Now, a dose-finding study for EPs-7630 was performed in children and adolescents. Methods:, A total of 400 patients (aged 6,18 years) were randomized to receive either 30 mg, 60 mg or 90 mg EPs-7630 or placebo daily. Primary outcome criterion was the change in the Bronchitis Severity Score (BSS) from day 0 to day 7. Results:, After 7 days of treatment, the change in the BSS total score was significantly better in the 60 mg and 90 mg groups compared with placebo that of the without relevant differences between these two dosages. Especially ,coughing', ,sputum' and ,rales at auscultation' improved under EPs-7630. Onset of effect was faster, time of bed rest shorter and treatment outcome and satisfaction with treatment were rated better. Tolerability was comparable with placebo in all treatment groups. Conclusion:, EPs-7630 is effective in acute bronchitis outside the strict indication for antibiotics in 6,18 years old patients, with a dose of 60 mg or 90 mg daily offering the best benefit/risk ratio. EPs-7630 significantly reduces the severity of symptoms, leads to a more favourable course of the disease and a faster recovery from acute bronchitis compared with the placebo, and is well tolerated. [source] | ||||||||||